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P.E.I. man in custody following six-hour standoff

A man is in custody following a six-hour standoff in eastern Prince Edward Island that started when police responded to a domestic dispute that quickly escalated when officers learned the suspect could be armed.




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Pentagon Opens Probe Into Sexual Abuse by U.S. Allies in Afghanistan

The Defense Department's Inspector General has opened an investigation into whether U.S. troops were discouraged from reporting the rape and sexual abuse of children by their Afghan allies.




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Inheritance

The Lockerbie bombing left only fragments of David Dornstein's life behind, but their discovery gave his brother a new purpose -- to gather what went missing, preserve what was left, and work to make sense of it all. That story is told in this special interactive presentation.




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ISIS in Afghanistan: School of Jihad

The emergence of ISIS in Afghanistan has introduced a new level of brutality to the conflict, beyond what has been practiced by the Taliban.




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“The Most Risky … Job Ever.” Reporting on “ISIS in Afghanistan”

Najibullah Quraishi has covered the war in Afghanistan for more than a decade, but embedding with ISIS fighters who've recently emerged there "was the most risky and dangerous job ever I've done in my life," he says.




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ISIS is in Afghanistan, But Who Are They Really?

It appears ISIS-allied fighters are gaining a foothold in Afghanistan, but just how similar are they to the group's branches in Iraq and Syria?




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Cobie Smulders sings social distance 'Let's Go to the Mall' parody

The coronavirus pandemic has many of us nostalgic for a simpler time — maybe when we were teenagers and/or watching our favorite early oughts sitcoms. 

Actress Cobie Smulders seems to be feeling that itch, and sensed we are too. The former How I Met Your Mother actress decided to recreate her character Robin Scherbatsky's hit song from the series, "Let's Go to The Mall."

For those who need a refresher, "Let's Go to The Mall" was released during Robin's short career as a pop star (under the name Robin Sparkles) in her homeland of Canada. While it has all the flair of an '80s banger — jelly bracelets, worshipping the mall — it was released in the '90s because apparently that's when '80s culture reached CanadaRead more...

More about How I Met Your Mother, Cobie Smulders, Movies Tv Shows, Social Distancing, and Entertainment




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The unreasonable importance of data preparation

In a world focused on buzzword-driven models and algorithms, you’d be forgiven for forgetting about the unreasonable importance of data preparation and quality: your models are only as good as the data you feed them. This is the garbage in, garbage out principle: flawed data going in leads to flawed results, algorithms, and business decisions. […]




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Trudeau says Canada will not pay full price for 8 million sub-standard masks

Prime Minister Justin Trudeau says Canada will not pay the full price for medical masks that do not live up to medical standards.





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Article: Five Stats to Understand Christmas in Japan

Christmas is not an official holiday in Japan, nor a widely observed religious holiday, but it is celebrated nonetheless in its own unique way. Here's some data that highlights Christmas in Japan.




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School bus drivers take on a new role to help students with distance learning

School bus drivers in the Upper Grand District School Board are transporting school work instead of students.




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Spectral and photochemical diversity of tandem cysteine cyanobacterial phytochromes [Plant Biology]

The atypical trichromatic cyanobacterial phytochrome NpTP1 from Nostoc punctiforme ATCC 29133 is a linear tetrapyrrole (bilin)-binding photoreceptor protein that possesses tandem-cysteine residues responsible for shifting its light-sensing maximum to the violet spectral region. Using bioinformatics and phylogenetic analyses, here we established that tandem-cysteine cyanobacterial phytochromes (TCCPs) compose a well-supported monophyletic phytochrome lineage distinct from prototypical red/far-red cyanobacterial phytochromes. To investigate the light-sensing diversity of this family, we compared the spectroscopic properties of NpTP1 (here renamed NpTCCP) with those of three phylogenetically diverged TCCPs identified in the draft genomes of Tolypothrix sp. PCC7910, Scytonema sp. PCC10023, and Gloeocapsa sp. PCC7513. Recombinant photosensory core modules of ToTCCP, ScTCCP, and GlTCCP exhibited violet-blue–absorbing dark-states consistent with dual thioether-linked phycocyanobilin (PCB) chromophores. Photoexcitation generated singly-linked photoproduct mixtures with variable ratios of yellow-orange and red-absorbing species. The photoproduct ratio was strongly influenced by pH and by mutagenesis of TCCP- and phytochrome-specific signature residues. Our experiments support the conclusion that both photoproduct species possess protonated 15E bilin chromophores, but differ in the ionization state of the noncanonical “second” cysteine sulfhydryl group. We found that the ionization state of this and other residues influences subsequent conformational change and downstream signal transmission. We also show that tandem-cysteine phytochromes present in eukaryotes possess similar amino acid substitutions within their chromophore-binding pocket, which tune their spectral properties in an analogous fashion. Taken together, our findings provide a roadmap for tailoring the wavelength specificity of plant phytochromes to optimize plant performance in diverse natural and artificial light environments.




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Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance [Molecular Bases of Disease]

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.




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Structure-based discovery of a small-molecule inhibitor of methicillin-resistant Staphylococcus aureus virulence [Molecular Biophysics]

The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.




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Oman’s New Sultan Needs to Take Bold Economic Steps

16 January 2020

Dr John Sfakianakis

Associate Fellow, Middle East and North Africa Programme
The country is in a good regional position, but the economy is at a crossroads.

2020-01-16-SultanHaitham2.jpg

Sultan Haitham bin Tariq speaks during a swearing in ceremony as Oman's new leader. Photo: Getty Images.

The transition of power in Oman from the deceased Sultan Qaboos to his cousin and the country’s new ruler, Sultan Haitham bin Tariq, has been smooth and quick, but the new sultan will soon find that he has a task in shoring up the country’s economic position.

Above all, the fiscal and debt profile of the country requires careful management. Fiscal discipline was rare for Oman even during the oil price spike of the 2000s. Although oil prices only collapsed in 2014, Oman has been registering a fiscal deficit since 2010, reaching a 20.6 per cent high in 2016. As long as fiscal deficits remain elevated, so will Oman’s need to finance those deficits, predominately by borrowing in the local and international market.

Oman’s Debt-to-GDP ratio has been rising at a worrying pace, from 4.9 per cent in 2014 to an IMF-estimated 59.8 per cent in 2019. By 2024, the IMF is forecasting the ratio to reach nearly 77 per cent. A study by the World Bank found that if the debt-to-GDP ratio in emerging markets exceeds 64 per cent for an extended period, it slows economic growth by as much as 2 per cent each year.

Investors are willing to lend to Oman, but the sultanate is paying for it in terms of higher spreads due to the underlying risk markets are placing on the rising debt profile of the country. For instance, Oman has a higher sovereign debt rating than Bahrain yet markets perceive it to be of higher risk, making it costlier to borrow. Failure to address the fiscal and debt situation also risks creating pressure on the country’s pegged currency.

If oil revenues remain low, Sultan Haitham will have to craft a daring strategy of diversification and private sector growth. He is well placed for this: Sultan Haitham headed Oman’s Vision 2040, which set out the country’s future development plans and aspirations, the first Gulf country to embark on such an assessment. However, like all vision documents in the Gulf, Oman’s challenge will be implementation.

In the age of climate change, renewable energy is a serious economic opportunity, which Oman has to keep pursuing. If cheap electricity is generated it could also be exported to other Gulf states and to south Asia. In Oman, the share of renewables in total electricity capacity was around 0.5 per cent in 2018; the ambition is to reach 10 per cent by 2025.

However, in order to reach this target, Oman would have to take additional measures such as enhancing its regulatory framework, introducing a transparent and gradual energy market pricing policy and integrating all stakeholders, including the private sector, into a wider national strategy.

Mining could provide another economic opportunity for Oman’s diversification efforts, with help from a more robust mining law passed last year. The country has large deposits of metals and industrial minerals and its mountains could have gold, palladium, zinc, rare earths and manganese.

Oman’s strategic location connecting the Gulf and Indian Ocean with east Africa and the Red Sea could also boost the country’s economy. The Duqm special economic zone, which is among the largest in the world, could become the commercial thread between Oman, south Asia and China’s ‘Belt and Road Initiative.’

Oman has taken important steps to make its economy more competitive and conducive to foreign direct investment. Incentives include a five-year renewable tax holiday, subsidized plant facilities and utilities, and custom duties relief on equipment and raw materials for the first 10 years of a firm’s operation in Oman.

A private sector economic model that embraces small- and medium-sized enterprises as well as greater competition and entrepreneurship would help increase opportunities in Oman. Like all other Gulf economies, future employment in Oman will have to be driven be the private sector, as there is little space left to grow the public sector.

Privatization needs to continue. Last year’s successful sale of 49 per cent of the electricity transmission company to China’s State Grid is a very positive step. The electricity distribution company as well as Oman Oil are next in line for some form of partial privatization.

The next decade will require Oman to be even more adept in its competitiveness as the region itself tries to find its new bearings. Take tourism for instance; Oman hopes to double its contribution to GDP from around 3 per cent today to 6 per cent by 2040 and the industry is expected to generate half a million jobs by then. Over the next 20 years, Oman will most likely be facing stiff competition in this area not only by the UAE but by Saudi Arabia as well.

The new sultan has an opportunity to embark on deeper economic reforms that could bring higher growth, employment opportunities and a sustainable future. But he has a big task.




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Webinar: Are the Gulf Standoffs Resolvable?

Research Event

21 April 2020 - 1:00pm to 2:00pm

Event participants

David Roberts, Assistant Professor and School of Security Studies Lead for Regional Security and Development, King's College London
Kristian Coates Ulrichsen, Associate Fellow, Middle East and North Africa Programme, Chatham House
Chair: Sanam Vakil, Deputy Director and Senior Research Fellow, Middle East and North Africa Programme, Chatham House

This webinar, part of the MENA Programme Webinar Series, will examine the trajectory of political and security dynamics in the Gulf in view of the ongoing rift within the Gulf Cooperation Council (GCC), the death of Sultan Qaboos in Oman, the escalation of tensions between Iran and the United States, and the COVID-19 crisis.

Speakers will explore the orientation of the GCC under a new Secretary-General and the prospects for mediation between Qatar and its neighbours, the future of Omani domestic and foreign policy under Sultan Haitham bin Tariq Al Said, eventual transitions to new leadership in Bahrain and Kuwait, and whether the impact of COVID-19 may help replace the confrontation within the GCC with closer coordination among its six member states.

The webinar will be livestreamed on the MENA Programme Facebook page.

Reni Zhelyazkova

Programme Coordinator, Middle East and North Africa Programme
+44 (0)20 7314 3624




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Radical new business model for pharmaceutical industry needed to avert antibiotic resistance crisis

7 October 2015

20151009Antibiotics.jpg

High-level complex of physiologically active antibiotic substance extracted from blastema at the Arctic Innovation Center (AIC) of Ammosov, North-Eastern Federal University (NEFU) in Yakutsk. Photo: Yuri Smityuk/ITAR-TASS Photo/Corbis.

Revenues for pharmaceutical companies need to be 'delinked' from sales of antibiotics to avoid their over-use and avert a public health crisis, says a new report from the think-tank Chatham House.

Over-use of antibiotics is contributing to the growing resistance of potentially deadly bacteria to existing drugs, threatening a public health crisis in the near future. The report notes that, by 2050, failing to tackle antibiotic resistance could result in 10 million premature deaths per year.                                       

Novel antibiotics to combat resistant pathogens are thus desperately needed, but market incentives are exacerbating the problem. Towards a New Global Business Model for Antibiotics: Delinking Revenues from Sales states that,                                       


'The current business model requires high levels of antibiotic use in order to recover the costs of R&D. But mitigating the spread of resistance demands just the opposite: restrictions on the use of antibiotics.'

                                       

To tackle this catch-22 problem, the Centre on Global Health Security at Chatham House recommends the establishment of a global body to implement a radical new business model for the industry, which would encourage investment and promote global access to - and conservation of - antibiotics.      

The current business model has several perverse effects. As R&D is an inherently risky and costly endeavour, the industry is chronically under-investing in new treatments. Today, few large pharmaceutical companies retain active antibacterial drug discovery programmes. Re-stoking the industry's interest in antibiotics would be one of the primary roles of the new body.   

Secondly, the need to recover sunk cost under the current business model encourages both high prices and over-marketing of successful drugs, making potentially life-saving treatments unaffordable to many in developing countries, while simultaneously encouraging over-use in developed markets and increasing resistance.   

The new global body would address these challenges by ‘delinking’ pharmaceutical revenues from sales of antibiotics. It would do this by directly financing the research and development of new drugs, which it would then acquire at a price based on production costs rather than the recovery of R&D expenses. Acquisition could take the form of procurement contracts with companies, the purchase of full IP rights or other licensing mechanisms.                                       

This would enable it to promote global access to antibiotics while simultaneously restricting over-use. Conservation would be promoted through education, regulation and good clinical practice, with the report recommending that 'proven conservation methods such as antibiotic stewardship programmes… be incentivized and implemented immediately.'

Priorities for R&D financing would be based on a comprehensive assessment of  threats arising from resistance. Antibiotics would qualify for the highest level of financial incentives if they combat resistant pathogens posing a serious threat to human health.                                       

Finance for the new body would come from individual nation states, with the report noting that this could 'begin with a core group of countries with significant research activity and large antibiotic markets, (though) it is envisaged that all high income countries should make an appropriate financial contribution.'                                 

It is not yet clear exactly how much funding would be necessary to combat resistance, but with inaction expected to cost $100 trillion in cumulative economic damage, the report argues that 'an additional global investment of up to $3.5 billion a year (about 10 per cent of the current value of global sales of antibiotics) would be a bargain.'

Editor's notes

Towards a New Global Business Model for Antibiotics: Delinking Revenues from Sales, is a Chatham House report edited by Charles Clift, Unni Gopinathan, Chantal Morel, Kevin Outterson, John-Arne Røttingen and Anthony So.

The report is embargoed until 00.01 GMT Friday 9 October.

For more information, or to request an interview with the editors, contact the press office.

Contacts

Press Office

+44 (0)20 7957 5739




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First ever global analysis of refugees’ energy use: High costs and poor supply undermine humanitarian assistance

11 November 2015

20151119MovingEnergyInitiative.jpg

A migrant girl looks at a light illuminating a camp site of refugees and migrants on the Greek island of Lesbos, 4 October 2015. Photo: Getty Images.

About 90 per cent of refugees living in camps have no access to electricity and many lack any form of lighting at night, says a Chatham House report for the Moving Energy Initiative. Energy poverty in refugee settlements is not on the radar of international initiatives and humanitarian agencies are ill-equipped to deal with the scale of need. 

Heat Light and Power for Refugees: Saving Lives, Reducing Costs zooms in on the energy needs of refugees and displaced people worldwide, and presents the first ever estimates of the volume and costs of what they use.

'The problem goes beyond electricity. 80 per cent of those in camps rely on firewood for cooking and, as a result, we estimate that some 20,000 people die prematurely each year due to the pollution from indoor fires. Exposure to extremes of cold and heat are also killers for people living in flimsy, temporary shelter,' says Glada Lahn, senior research fellow at Chatham House. 'The current lack of provision for energy undermines the fundamental aims of humanitarian assistance,' she adds.

There are nearly 60 million forcibly displaced people in the world, and they pay staggering costs for energy. The 83,277 households living in Dadaab in Kenya, the world’s largest refugee settlement, spent an estimated $6.2 million on firewood last year, which accounts for approximately 24 per cent of their overall household income. (The average UK household spent 4 per cent of its income on energy in 2011.) In Uganda, almost half of refugee households surveyed by the UNHCR skip meals because they do not have enough fuel to cook with.

'The imperative is to find humane, creative and cost-effective ways to respond to the needs of so many individuals, most of whom are women and children.  Improving access to clean, safe and sustainable energy offers a promising way forward,' says Kofi Annan in the report’s foreword.

The report calls for an overhaul in the way that heat, light and power are delivered in humanitarian crises. It makes the case for new partnerships between humanitarian agencies and private providers to increase clean energy access in refugee settlements. Investment in energy infrastructure will also benefit host communities in some of the world’s poorest countries.

'As refugee households spend approximately $2.1 billion on energy each year, developing local markets for energy services could be part of a mix of solutions,' adds Lahn. 'Using green, culturally appropriate technologies could save lives, reduce CO2 emissions by 11 million tonnes per year and radically improve living standards. Introducing even the most basic solutions, such as improved cookstoves and basic solar lanterns, could save $323 million a year in fuel costs.' 

Other findings include:

  • Rape and violence against women is common in many unlit camps. Only 4 per cent of women and girls in households in the Goudoubo camp in Burkina Faso would go out after dark due to the lack of streetlights.
  • Wood equalling around 49,000 football pitches worth of forest (64,700 acres) is burned by displaced families living in camps each year, mainly in countries suffering severe deforestation, because they have no alternative sources of energy.
  • Firewood consumption emits nearly twice as much CO2 as liquid petroleum gas and produces little energy in comparison to its carbon intensity.

International Development Minister Grant Shapps said:

‘Across sub-Saharan Africa, hundreds of millions of people still do not have access to electricity. Women and girls are at risk of violence after dark, families are forced to inhale toxic kerosene fumes, and energy remains unaffordable for many.

‘With the technology in place and investors coming on board, the time to act is now. The UK's Energy Africa campaign is already kick-starting a solar revolution across the continent.

‘Supporting the Moving Energy Initiative is another way Britain can help boost access to clean, reliable and affordable energy. This will transform people’s lives and help achieve the UN’s goal of universal energy access by 2030.’

Editor's notes

  • Read Heat Light and Power for Refugees: Saving Lives, Reducing Costs by Glada Lahn and Owen Grafham.
  • To link back to the report in an article, please use this landing page for the final report.
  • The Moving Energy Initiative (MEI) is a collaboration between GVEP International, Chatham House, Practical Action Consulting, the Norwegian Refugee Council (NRC) and the United Nations High Commissioner for Refugees (UNHCR). The report is supported by the UK Department for International Development through the Humanitarian Innovation and Evidence Programme.
  • The number of refugee households in Dadaab, Kenya is as of May 2015.
  • Chatham House will host a press briefing with MEI programme board member Michael Keating and authors Glada Lahn and Owen Grafham on Thursday 12 November at 10:30-11:30 GMT. To register, or for interview requests, please contact the press office.
  • All figures are original and based on estimations and calculations prepared for the Moving Energy Initiative. Chatham House designed a model offering the first estimates of the scale and cost of energy use and CO2 emissions among forcibly displaced households worldwide, not including people affected by natural disasters. For more details on the populations considered in the report and used in the model, contact the authors.
  • The authors are available to answer questions from the media. Please contact the press office.

Contacts

Press Office

+44 (0)20 7957 5739




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Chatham House awarded Prospect magazine’s Think-Tank of the Year

29 November 2016

Chatham House named think-tank of the year at Prospect magazine’s annual think-tank awards.

landscape Robin award.jpg

Chatham House named Think-Tank of the Year. Photo: Visual Eye.

Chatham House has been named Prospect magazine’s Think-Tank of the Year at a ceremony in the Houses of Parliament. The institute was also the winner in the UK categories for International Affairs and Energy and Environment. The quality, credibility and impact of Chatham House’s research was acknowledged for helping to create better understanding of key global phenomena at this critical time in world affairs. The judges commented that the institute’s work is ‘reliably excellent’ and a ‘gold standard of knowledge and professionalism’.  

Specifically, the US and the Americas and Asia programmes’ joint report Asia-Pacific Power Balance: Beyond the US-China Narrative, by Xenia Wickett, John Nilsson-Wright and Tim Summers, was singled out for being an important resource to help explain the developing geopolitical relationship between the United States and China.

The Energy, Environment and Resources department’s livestock project was a major factor in their award in the Energy & Environment UK category, including the report Changing Climate, Changing Diets: Pathways to Lower Meat Consumption by Laura Wellesley, Antony Froggatt and Catherine Happer, which developed recommendations for how dietary change can be effected in different national and cultural contexts.

Dr Robin Niblett, director of Chatham House said ‘The integrity and authority of Chatham House’s research is needed more than ever and I am extremely proud of our staff and their work particularly during this difficult and challenging year in world affairs’.




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Reviewing Antimicrobial Resistance: Where Are We Now and What Needs to Be Done?

Research Event

8 October 2019 - 10:30am to 12:00pm

RSA House, 8 John Adam Street, London, WC2N 6EZ

Event participants

Tim Jinks, Head of Drug-Resistant Infections Programme, Wellcome
Jim O’Neill, Chair, Review on Antimicrobial Resistance; Chair, Chatham House
Haileyesus Getahun, Director of Global Coordination and Partnership on Antimicrobial Resistance, World Health Organization 
Juan Lubroth, Chief Veterinary Officer, Food and Agriculture Organization (Videolink)
Jyoti Joshi, Head, South Asia, Center for Disease Dynamics, Economics & Policy
Estelle Mbadiwe, Coordinator-Nigeria, Global Antibiotic Resistance Partnership
Charles Clift, Senior Consulting Fellow, Chatham House; Report Author

The Review on Antimicrobial Resistance, chaired by Jim O’Neill, was commissioned by former UK prime minister, David Cameron, in July 2014. Supported by the UK government and the Wellcome Trust, the final report of the review was published in May 2016 and has had a global impact in terms of motivating political leaders and decision-makers to take more seriously the threat posed by antimicrobial resistance.

Yet there is now a perception that the political momentum to address the issue is waning and needs to be reinvigorated.

In a further report produced by Chatham House, the progress of the recommendations of the review is assessed and the key ways to move forward are identified.

Panellists at this event, where highlights of the report are presented, provide their assessment of the progress so far and discuss priorities for future action.

The report was funded by Wellcome.

Alexandra Squires McCarthy

Programme Coordinator, Global Health Programme
+44 (0)207 314 2789




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A Tandem Affinity Tag for Two-step Purification under Fully Denaturing Conditions: Application in Ubiquitin Profiling and Protein Complex Identification Combined with in vivoCross-Linking

Christian Tagwerker
Apr 1, 2006; 5:737-748
Research




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The Paragon Algorithm, a Next Generation Search Engine That Uses Sequence Temperature Values and Feature Probabilities to Identify Peptides from Tandem Mass Spectra

Ignat V. Shilov
Sep 1, 2007; 6:1638-1655
Technology




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Highly Selective Enrichment of Phosphorylated Peptides from Peptide Mixtures Using Titanium Dioxide Microcolumns

Martin R. Larsen
Jul 1, 2005; 4:873-886
Technology




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The cytochrome P450 enzyme CYP24A1 increases proliferation of mutant KRAS-dependent lung adenocarcinoma independent of its catalytic activity [Cell Biology]

We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell synchronization and biochemical experiments in lung adenocarcinoma cells, revealing a link between CYP24A1 and anaphase-promoting complex (APC), a key cell cycle regulator. We demonstrate that CYP24A1 expression is cell cycle–dependent; it was higher in the G2-M phase and diminished upon G1 entry. CYP24A1 has a functional destruction box (D-box) motif that allows binding with two APC adaptors, CDC20-homologue 1 (CDH1) and cell division cycle 20 (CDC20). Unlike other APC substrates, however, CYP24A1 acted as a pseudo-substrate, inhibiting CDH1 activity and promoting mitotic progression. Conversely, overexpression of a CYP24A1 D-box mutant compromised CDH1 binding, allowing CDH1 hyperactivation, thereby hastening degradation of its substrates cyclin B1 and CDC20, and accumulation of the CDC20 substrate p21, prolonging mitotic exit. These activities also occurred with a CYP24A1 isoform 2 lacking the catalytic cysteine (Cys-462), suggesting that CYP24A1's oncogenic potential is independent of its catalytic activity. CYP24A1 degradation reduced clonogenic survival of mutant KRAS-driven lung cancer cells, and calcitriol treatment increased CYP24A1 levels and tumor burden in Lsl-KRASG12D mice. These results disclose a catalytic activity-independent growth-promoting role of CYP24A1 in mutant KRAS-driven lung cancer. This suggests that CYP24A1 could be therapeutically targeted in lung cancers in which its expression is high.




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Noncatalytic Bruton's tyrosine kinase activates PLC{gamma}2 variants mediating ibrutinib resistance in human chronic lymphocytic leukemia cells [Membrane Biology]

Treatment of patients with chronic lymphocytic leukemia (CLL) with inhibitors of Bruton's tyrosine kinase (BTK), such as ibrutinib, is limited by primary or secondary resistance to this drug. Examinations of CLL patients with late relapses while on ibrutinib, which inhibits BTK's catalytic activity, revealed several mutations in BTK, most frequently resulting in the C481S substitution, and disclosed many mutations in PLCG2, encoding phospholipase C-γ2 (PLCγ2). The PLCγ2 variants typically do not exhibit constitutive activity in cell-free systems, leading to the suggestion that in intact cells they are hypersensitive to Rac family small GTPases or to the upstream kinases spleen-associated tyrosine kinase (SYK) and Lck/Yes-related novel tyrosine kinase (LYN). The sensitivity of the PLCγ2 variants to BTK itself has remained unknown. Here, using genetically-modified DT40 B lymphocytes, along with various biochemical assays, including analysis of PLCγ2-mediated inositol phosphate formation, inositol phospholipid assessments, fluorescence recovery after photobleaching (FRAP) static laser microscopy, and determination of intracellular calcium ([Ca2+]i), we show that various CLL-specific PLCγ2 variants such as PLCγ2S707Y are hyper-responsive to activated BTK, even in the absence of BTK's catalytic activity and independently of enhanced PLCγ2 phospholipid substrate supply. At high levels of B-cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically-inactive BTK restored the ability of the BCR to mediate increases in [Ca2+]i. Because catalytically-inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving the noncatalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs.




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Spectral and photochemical diversity of tandem cysteine cyanobacterial phytochromes [Plant Biology]

The atypical trichromatic cyanobacterial phytochrome NpTP1 from Nostoc punctiforme ATCC 29133 is a linear tetrapyrrole (bilin)-binding photoreceptor protein that possesses tandem-cysteine residues responsible for shifting its light-sensing maximum to the violet spectral region. Using bioinformatics and phylogenetic analyses, here we established that tandem-cysteine cyanobacterial phytochromes (TCCPs) compose a well-supported monophyletic phytochrome lineage distinct from prototypical red/far-red cyanobacterial phytochromes. To investigate the light-sensing diversity of this family, we compared the spectroscopic properties of NpTP1 (here renamed NpTCCP) with those of three phylogenetically diverged TCCPs identified in the draft genomes of Tolypothrix sp. PCC7910, Scytonema sp. PCC10023, and Gloeocapsa sp. PCC7513. Recombinant photosensory core modules of ToTCCP, ScTCCP, and GlTCCP exhibited violet-blue–absorbing dark-states consistent with dual thioether-linked phycocyanobilin (PCB) chromophores. Photoexcitation generated singly-linked photoproduct mixtures with variable ratios of yellow-orange and red-absorbing species. The photoproduct ratio was strongly influenced by pH and by mutagenesis of TCCP- and phytochrome-specific signature residues. Our experiments support the conclusion that both photoproduct species possess protonated 15E bilin chromophores, but differ in the ionization state of the noncanonical “second” cysteine sulfhydryl group. We found that the ionization state of this and other residues influences subsequent conformational change and downstream signal transmission. We also show that tandem-cysteine phytochromes present in eukaryotes possess similar amino acid substitutions within their chromophore-binding pocket, which tune their spectral properties in an analogous fashion. Taken together, our findings provide a roadmap for tailoring the wavelength specificity of plant phytochromes to optimize plant performance in diverse natural and artificial light environments.




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Understanding the dynamics of the Indo-Pacific: US–China strategic competition, regional actors, and beyond

6 November 2019 , Volume 96, Number 1

The first issue of International Affairs in 2020 explores the geopolitics of the 'Indo-Pacific' region.

Kai He and Mingjiang Li

As a geographical concept, ‘Indo-Pacific’ has existed for decades. As a political and strategic concept, it has since 2010 gradually become established in the foreign policy lexicon of some countries, especially Australia, India, Japan and the United States. However, China seems to be reluctant to identify itself as part of the Indo-Pacific; Chinese leaders believe that the US-led Indo-Pacific strategy aims to contain China's rise. While the battle between the two geographical concepts ‘Indo-Pacific’ and ‘Asia–Pacific’ may be fairly easily settled in the future, US–China strategic competition has just begun. Will the Indo-Pacific become a battlefield for US–China rivalry? How will China cope with the US ‘free and open Indo-Pacific’ (FOIP) strategy? How will other regional actors respond to the US–China strategic competition in the Indo-Pacific? What are the strategic implications of the ‘Indo-Pacific’ concept for regional order transformation? How will the Indo-Pacific be institutionalized, economically, politically and strategically? This article introduces the January 2020 special issue of International Affairs, which aims to address those questions, using both country-specific and regional perspectives. Seven articles focus on the policy responses of major players (Australia, China, India, Indonesia, Japan and ASEAN) to the US FOIP strategy and related US–China rivalry in the region. A further three articles examine the profound implications of Indo-Pacific dynamics for regional institution-building and for geopolitical and geo-economic architecture.




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Webinar: Are the Gulf Standoffs Resolvable?

Research Event

21 April 2020 - 1:00pm to 2:00pm

Event participants

David Roberts, Assistant Professor and School of Security Studies Lead for Regional Security and Development, King's College London
Kristian Coates Ulrichsen, Associate Fellow, Middle East and North Africa Programme, Chatham House
Chair: Sanam Vakil, Deputy Director and Senior Research Fellow, Middle East and North Africa Programme, Chatham House

This webinar, part of the MENA Programme Webinar Series, will examine the trajectory of political and security dynamics in the Gulf in view of the ongoing rift within the Gulf Cooperation Council (GCC), the death of Sultan Qaboos in Oman, the escalation of tensions between Iran and the United States, and the COVID-19 crisis.

Speakers will explore the orientation of the GCC under a new Secretary-General and the prospects for mediation between Qatar and its neighbours, the future of Omani domestic and foreign policy under Sultan Haitham bin Tariq Al Said, eventual transitions to new leadership in Bahrain and Kuwait, and whether the impact of COVID-19 may help replace the confrontation within the GCC with closer coordination among its six member states.

The webinar will be livestreamed on the MENA Programme Facebook page.

Reni Zhelyazkova

Programme Coordinator, Middle East and North Africa Programme
+44 (0)20 7314 3624




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Kazakhstan's Foreign Policy Priorities

Research Event

21 November 2013 - 2:00pm to 3:00pm

Chatham House, London

Event participants

Erlan Idrissov, Minister of Foreign Affairs, Kazakhstan

Kazakhstan has attracted international attention due to its energy resources, its relative openness to foreign investment and its proximity to Afghanistan, all of which influence its foreign policy. The withdrawal of ISAF forces from the region in 2014 and Kazakhstan's participation in a number of regional and international initiatives are also likely to play a role in shaping the country's foreign policy in the short to medium term.

Mr Idrissov will outline the main items on Astana's foreign policy agenda for approximately 15 minutes, followed by 45 minutes for questions and discussion.

Attendance is by invitation only. 




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Building Resistance to Violent Extremism




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The United States in Afghanistan and Pakistan




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Talking to North Korea: Ending the Nuclear Standoff?




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Martin Wight Memorial Lecture: The Future of Think-Tanks




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Frosty Neighbours? Unpacking Narratives of Afghanistan-Pakistan Relations




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Undercurrents: Episode 23 - Robin Niblett on the Future of Think-Tanks




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Afghanistan in 2018: A Survey of the Afghan People




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Jihad and Terrorism in Pakistan: The Case of Lashkar-e-Taiba




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Understanding South Africa's Political Landscape




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Kazakhstan: Tested by Transition




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Undercurrents: Episode 45 - Politics in Kazakhstan, and Youth Engagement in Politics




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Understanding Decolonization in the 21st Century




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Undercurrents: Episode 46 - Understanding Decolonization, and China’s Response to Coronavirus




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Undercurrents: Episode 47 - Pakistan's Blasphemy Laws




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Quantitative Profiling of the Human Substantia Nigra Proteome from Laser-capture Microdissected FFPE Tissue [Research]

Laser-capture microdissection (LCM) allows the visualization and isolation of morphologically distinct subpopulations of cells from heterogeneous tissue specimens. In combination with formalin-fixed and paraffin-embedded (FFPE) tissue it provides a powerful tool for retrospective and clinically relevant studies of tissue proteins in a healthy and diseased context. We first optimized the protocol for efficient LCM analysis of FFPE tissue specimens. The use of SDS containing extraction buffer in combination with the single-pot solid-phase-enhanced sample preparation (SP3) digest method gave the best results regarding protein yield and protein/peptide identifications. Microdissected FFPE human substantia nigra tissue samples (~3,000 cells) were then analyzed, using tandem mass tag (TMT) labeling and LC-MS/MS, resulting in the quantification of >5,600 protein groups. Nigral proteins were classified and analyzed by abundance, showing an enrichment of extracellular exosome and neuron-specific gene ontology (GO) terms among the higher abundance proteins. Comparison of microdissected samples with intact tissue sections, using a label-free shotgun approach, revealed an enrichment of neuronal cell type markers, such as tyrosine hydroxylase and alpha-synuclein, as well as proteins annotated with neuron-specific GO terms. Overall, this study provides a detailed protocol for laser-capture proteomics using FFPE tissue and demonstrates the efficiency of LCM analysis of distinct cell subpopulations for proteomic analysis using low sample amounts.




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Structure-based discovery of a small-molecule inhibitor of methicillin-resistant Staphylococcus aureus virulence [Molecular Biophysics]

The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.




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Will a Devastating Bushfire Season Change Australia’s Climate Stance?

23 January 2020

Madeleine Forster

Richard and Susan Hayden Academy Fellow, International Law Programme

Professor Tim Benton

Research Director, Emerging Risks; Director, Energy, Environment and Resources Programme
With Australians experiencing first-hand the risks of climate change, Madeleine Forster and Tim Benton examine the influencers, at home or abroad, that could push the government towards more action.

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Residents look on as flames burn through bush on 4 January 2020 in Lake Tabourie, NSW. Photo: Getty Images.

The 2019–20 fire season in Australia has been unprecedented. To date, an estimated 18 million hectares of fire has cut swathes through the bush – an area greater than that of the average European country and over five times the size of blazes in the Amazon.

This reflects previous predictions of Australian science. Since 2008 and as recently as 2018, scientific bodies have warned that climate change will exacerbate existing conditions for fires and other climatic disasters in Australia. What used to be once-in-a-generation fires now re-appear within 10–15 years with increased ferocity, over longer seasons.

In a country known for climate denial and division, debate has erupted around bushfire management and climate change. One of these is whether controlled burns are the answer to Australia’s climate-affected fire conditions.

There is no single risk reduction strategy. Controlled burning remains key, if adapted to the environment and climate

But when three out of four seasons in a year can support destructive bushfires, there are clear limits to what controlled burning and other fire management techniques can achieve. Other ‘adaptation’ measures are also likely to provoke intense debate – including bush clearance. As one Australian expert offered to highlight where Australia has got to, families should probably not go on holiday to bush and beach during the height of summer when temperatures and fire risk peaks. 

So, unless Australia is prepared to debate radical changes to where people live and how land is used, the limits to adaptation imply the need for mitigation. This means supporting ambitious global greenhouse emissions reductions targets. As research from Victoria, one fire-prone state in Australia, highlights, ‘the emissions pathway we follow is the largest determinant of change to many variables [such as temperature] beyond the next few decades.’

Can Australia become a more active global partner on emissions?

Australia accounts for just over one per cent of global emissions, so reducing domestic emissions – even though on a per capita basis they are the highest in the world – will not reduce Australia’s climate risk. Showing international leadership and supporting a powerful coalition of the willing to tackle climate change is the only way ahead. By showing a willingness to adopt climate ambition, Australia can help more constructive worldwide action, and thereby reduce its own risk exposure. 

Leading by example is a politically difficult issue for Australia. Prime Minister Scott Morrison was re-elected in May 2019 on an economic stability platform, and a promise not to imperil employment growth through climate action. Australia has contested UN estimates that it will not meet its existing modest goals for domestic emissions, by seeking to rely on carryover credits from action under the Kyoto Protocol as proof of progress.

It has also distanced itself from concerns over global supply and demand in fossil fuels. Australia remains a global supplier for fossil fuels, including coal – the nation’s coal exports accounted for $67 billion in revenues in 2019 in an expanding but changing Asian market, supplying ‘some of the cheapest electricity in the world’.

Possible influencers of change

With Australians experiencing first-hand the risks of climate change, there is already pressure to do more. Many are sceptical this will translate into domestic targets or export policies that give Australia the moral authority to ask for more action on the global stage.

Here, diverse groups who share a common interest in seeing Australia recover from the bushfires and address future climate risks could be key.

Importantly this includes rural and urban-fringe communities affected by the bushfires. They were part of Morrison’s traditional supporter-base but are angry at the government’s handling of the crisis and increasingly see how tiptoeing around emissions (including exports) has also ‘buried’ open discussion at home on climate-readiness.

Australian states could also find themselves taking a lead role. Virtually all jurisdictions have now committed to their own goals, most based on zero-carbon goals by 2050 (as has New Zealand). These can support modelling for Australia’s energy transition from coal, through gas, to market competitive renewables, while also help to ensure this reflects community expectations on jobs, electricity prices and other costs. 

Other emerging voices include the insurance and banking sectors (the Reserve Bank of Australia warned of the long-term financial stability risks of climate change before the fires) and indigenous Australians (one group of Torres Strait Islanders have filed a complaint to the UN Human Rights Committee which, if heard, will place Australia’s emissions record under the spotlight again). Their challenge now is finding a common language on what a cohesive approach to addressing climate change risk looks like. 

The international picture is mixed. The United States’ poor federal climate policy is a buffer for Australia. French President Emmanuel Macron has tried to raise the cost of inaction for Australia in current EU–Australia trade negotiations, but many large emitters in the Indo-Pacific region remain key Australian trading partners, investors and buyers of Australian coal. 

In the meantime, the United Kingdom is preparing for the meeting of parties to the Paris Agreement in Glasgow in November. A key global event following Brexit, the UK will no doubt be hoping to encourage a leadership circle with national commitments that meet global need to make the Glasgow meeting a success.

The UK public has expressed enormous sympathy for Australia in the bushfires and outrage over ‘climate denialism.’ Australia’s experience will be a cautionary tale of the effects of climate change at the meeting. Could the UK also support Australia to become a less reluctant partner in global climate action?




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Reviewing Antimicrobial Resistance: Where Are We Now and What Needs to Be Done?

Research Event

8 October 2019 - 10:30am to 12:00pm

RSA House, 8 John Adam Street, London, WC2N 6EZ

Event participants

Tim Jinks, Head of Drug-Resistant Infections Programme, Wellcome
Jim O’Neill, Chair, Review on Antimicrobial Resistance; Chair, Chatham House
Haileyesus Getahun, Director of Global Coordination and Partnership on Antimicrobial Resistance, World Health Organization 
Juan Lubroth, Chief Veterinary Officer, Food and Agriculture Organization (Videolink)
Jyoti Joshi, Head, South Asia, Center for Disease Dynamics, Economics & Policy
Estelle Mbadiwe, Coordinator-Nigeria, Global Antibiotic Resistance Partnership
Charles Clift, Senior Consulting Fellow, Chatham House; Report Author

The Review on Antimicrobial Resistance, chaired by Jim O’Neill, was commissioned by former UK prime minister, David Cameron, in July 2014. Supported by the UK government and the Wellcome Trust, the final report of the review was published in May 2016 and has had a global impact in terms of motivating political leaders and decision-makers to take more seriously the threat posed by antimicrobial resistance.

Yet there is now a perception that the political momentum to address the issue is waning and needs to be reinvigorated.

In a further report produced by Chatham House, the progress of the recommendations of the review is assessed and the key ways to move forward are identified.

Panellists at this event, where highlights of the report are presented, provide their assessment of the progress so far and discuss priorities for future action.

The report was funded by Wellcome.

Alexandra Squires McCarthy

Programme Coordinator, Global Health Programme
+44 (0)207 314 2789




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Review of Progress on Antimicrobial Resistance

8 October 2019

A startling lack of progress on critical recommendations to tackle antimicrobial resistance is highlighted in this new global progress report, as well as opportunities for further action and key obstacles that need to be overcome.

Use the Download button to choose either the Research Paper, or the Background and Analysis Paper.

Dr Charles Clift

Senior Consulting Fellow, Global Health Programme

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A PhD student at Melbourne’s Doherty Institute inspects the superbug Staphylcocus epidermidis on an agar plate on 4 September 2018. Photo: Getty Images.
  • The 2016 Review on Antimicrobial Resistance has had a global impact: as an advocacy tool, in raising the profile of antimicrobial resistance (AMR) on the international agenda, and in helping to stimulate a number of new initiatives, in particular relating to the funding of early-stage research.
  • However, there has been very little progress on the review’s central and most expensive recommendations for transforming research and development incentives for antibiotics, vaccines and diagnostics.
  • There have been significant advances in reducing antibiotic use in agriculture, particularly in high-income countries, but there is a long way to go in low- and middle-income countries (LMICs).
  • There has been greater investment in awareness raising but questions remain about its impact and effectiveness in changing behaviour.
  • Proposals to restrict over-the-counter sales of antibiotics, as recommended by the Review, have foundered in the face of poor living conditions and access to healthcare in LMICs.
  • A major reason for the use of antibiotics in LMICs is the prevalence of unhygienic conditions in the community and in healthcare facilities, which contribute to infection and limit the impact of messages about awareness and infection prevention and control.
  • Providing quality healthcare to all and moving towards universal health coverage in LMICs will be crucial in addressing the problems of both adequate access to antibiotics and in restricting over-the-counter sales.
  • A greater emphasis on investments in water, sanitation and housing will be central to reducing reliance on antibiotics in LMICs in the longer term. This agenda should inform the operations of governments and funding agencies such as the International Monetary Fund (IMF) and the World Bank.
  • Investments have been made in improving surveillance of antibiotic use and resistance, particularly for humans, but more effort is required to create surveillance systems that provide data sufficiently accurate to influence policy and action. This applies also to antibiotics and resistant genes circulating in the environment.
  • The emerging innovations in the global governance of AMR need to lead to action rather than more words.